The extract of Saururus cernuus (a toxic aquatic weed) on fractionation gave a series of ten closely related compounds (SC-1, SC-2 ...) which appear to belong to the class of neolignans. Of these, SC-5, 7, 8 and 9 represent the toxic principles, with SC-8 being the major component. At nontoxic doses, SC-8 showed behavioral patterns in mice typical of a major tranquilizer. In further preliminary testing, it inhibited aggressive response and amphetamine-induced stereotypy in mice and raised prolactin levels. Its antiamphetamine ED50 of 0.3 mg/Kg (4.0 x 10 to the -7 M/Kg) makes it 20x as potent as chlorpromazine with about the same therapeutic index. It is alao active by the oral route. Although the structures of SC-5, 7, 8 and 9 are not yet elucidated, they represent the first instances of neolignans with neuroleptic activity and the first natural products to show such activity since reserpine. Also, unlike all the known neuroleptic drugs, these are not basic and have no nitrogen. They thus present a novel structure to the arena of neuroleptics and can have significant impact on the synthesis, mode of action and clinical use of neuroleptic drugs commonly used in schizophrenia. The objectives of the proposal are to isolate all the active priciples of the plant in quantities sufficient for structure elucidation and evaluation of their neuroleptic potential and provide a structure/activity profile, based on synthesis and/or transformation of the active neolignans. The extracts of the stems and roots will be fractionated based on the toxicity and all the toxic principles will be isolated using chromatographic methods including HPLC. The structures and stereochemistry will be elucidated by a combination of spectral and degradative methods. The active compounds will be tested in a series of behavioral tests in rodents most commonly used for evaluating neuroleptic drugs e.g., antagonism to amphetamine, apomorphine, norepinephrine and tryptamine, as well as selective binding to dopamine receptors. The four natural members and the proposed 'first line' analogues will provide a useful structure/activity profile and synthetic efforts on the active neolignans will be considered after the structural elucidation and evaluation.